P774: SUBSTANTIAL INCREASES IN PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) RED BLOOD CELL CLONE SIZE WITH ORAL IPTACOPAN MONOTHERAPY CONFIRMS CONTROL OF HEMOLYSIS IN COMPLEMENT INHIBITOR-NAÏVE PNH PATIENTS
Authors: Régis Peffault de Latour, Bing Han, Jaroslaw P Maciejewski, Yasutaka Ueda, Rong Fu, LI Zhang, Austin Kulasekararaj, Alexander Röth, Lee Ping Chew, Jun Ho Jang, Lily L L Wong, Jens Panse, Eng-Soo Yap, Luana Marano, Flore Sicre de Fontbrune, Chen Yang, Partha Banerjee, Zhixin Wang, Christine Thorburn, Shujie LI, Marion Dahlke, Antonio Maria Risitano
Journal: HemaSphere (2023)

Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background: Iptacopan, a first-in-class, oral, selective complement factor B inhibitor, recently demonstrated efficacy and safety in patients with PNH and anemia despite anti-C5 treatment in the Phase III randomized APPLY-PNH trial (NCT04558918) (Peffault de Latour et al. Blood 2022). In the single-arm, open-label, multicenter, Phase III APPOINT-PNH trial (NCT04820530), iptacopan monotherapy led to clinically meaningful hemoglobin (Hb) increases without the need for red blood cell transfusions (RBCTs) and control of intravascular hemolysis (IVH) in complement inhibitor-naïve patients with PNH (Risitano et al. EBMT 2023). Aims: We report total PNH red blood cell (RBC) clone size and C3 deposition data (type II plus type III PNH RBCs) from the 24-week core treatment period of the APPOINT-PNH trial. Methods: Complement inhibitor-naïve adult PNH patients who had mean Hb <10 g/dL and lactate dehydrogenase (LDH) >1.5 x upper limit of normal received iptacopan monotherapy 200 mg twice daily. The primary endpoint was response defined as a ≥2 g/dL Hb increase from baseline in the absence of RBCTs. The response probability was described as proportions of responders with 95% confidence intervals (CIs) calculated using bootstrap; Bayesian multiple imputation was used to account for missing data. Total PNH RBC clone size and C3 deposition were exploratory endpoints assessed by flow cytometry and analyzed using descriptive statistics. Results: Forty patients received iptacopan. The primary objective was met with an estimated 92.2% (95% CI 82.5,100) of patients achieving a ≥2 g/dL Hb increase from baseline in absence of RBCTs. An estimated 62.8% (95% CI 47.5, 77.5) and 97.6% (95% CI 92.5, 100) of patients achieved Hb ≥12 g/dL (in absence of RBCTs) and transfusion avoidance, respectively. Changes from baseline in Hb, LDH, absolute reticulocyte count and Functional Assessment of Chronic Illness Therapy – Fatigue scores were +4.28 g/dL (95% CI 3.87, 4.70), −83.55% (95% CI −84.90, −82.08), −82.48 x 109/L (95% CI −89.33, −75.62) and +10.75 (95% CI 8.66, 12.84), respectively. No clinical breakthrough hemolysis events or major adverse vascular events were observed during the core treatment period. With iptacopan monotherapy, the mean (standard deviation) change from baseline to Week 24 in total PNH RBC clone size was 43.2% (18.9); by Week 24, the total PNH RBC clone size increased to 87.1% of the total RBC population (Figure). As expected in complement inhibitor-naïve patients, mean C3 deposition was negligible at baseline (0.67%) and remained consistently low through Week 12 (0.05%) and Week 24 (0.11%). There were no deaths. The most frequent treatment-emergent adverse events were headaches (27.5%), COVID-19 (15.0%), upper respiratory tract infections (12.5%) and diarrhea (7.5%). No patients discontinued iptacopan.Summary/Conclusion: Single-agent, oral iptacopan led to clinically meaningful Hb increases without the need for RBCTs, demonstrating good control of IVH in most complement inhibitor-naïve patients with hemolytic PNH. Treatment with iptacopan monotherapy improved survival of PNH RBCs, indicated by an increase in total PNH RBC clone size; no clinical breakthrough hemolysis was reported during the core treatment period. No evidence of C3-mediated extravascular hemolysis was observed, supported by consistently low C3 deposition throughout the treatment period. Iptacopan exhibited a favorable safety profile. This single-arm, Phase III trial demonstrated that oral iptacopan monotherapy could become a potentially practice-changing outpatient and preferred therapeutic option for patients with hemolytic PNH. Keywords: Complement, Hemolysis, Paroxysmal nocturnal hemoglobinuria (PNH), Phase III